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US4180585A - Pharmacologically active enol esters - Google Patents

Pharmacologically active enol esters Download PDF

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Publication number
US4180585A
US4180585A US05/735,738 US73573876A US4180585A US 4180585 A US4180585 A US 4180585A US 73573876 A US73573876 A US 73573876A US 4180585 A US4180585 A US 4180585A
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US
United States
Prior art keywords
formula
naphthyl
methoxy
ene
acetoxybut
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
US05/735,738
Inventor
Alexander C. Goudie
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beecham Group PLC
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Beecham Group PLC
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Filing date
Publication date
Application filed by Beecham Group PLC filed Critical Beecham Group PLC
Priority to AR26971777A priority Critical patent/AR215654A1/en
Application granted granted Critical
Publication of US4180585A publication Critical patent/US4180585A/en
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
    • C07D317/14—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D317/18—Radicals substituted by singly bound oxygen or sulfur atoms
    • C07D317/20—Free hydroxyl or mercaptan
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present invention relates to naphthalene derivatives, to pharmaceutical compositions containing them and to the process for their preparation.
  • the present invention provides anti-inflammatory acetals, enol acylates and enol ethers of the compound of the formula (I): ##STR2##
  • the aforementioned derivatives of the compounds of formula (I) are those notionally derivable from C 1-8 alcohols or C 1-8 acids.
  • the aforementioned derivatives of the compounds of the formula (I) are those notionally derivable from C 2-4 alcohols or C 2-4 acids.
  • Particularly suitable compounds of this invention include those of the formulae (II)-(IV): ##STR3## wherein R 1 is an ethyl, propyl, acetyl or propionyl group; R 2 is an ethyl or propyl group and R 3 is an ethyl or propyl group or is joined to R 2 so that R 2 together with R 3 is a CH 2 CH 2 or CH 2 CH 2 CH 2 group.
  • the present invention also provides pharmaceutical compositions adapted for oral administration which comprise an anti-inflammatory compound of the invention together with a pharmaceutically acceptable carrier.
  • compositions of this invention may be in the form of tablets, capsules, solutions, suspensions, granules or the like or any other dosage form conventionally used for the oral administration of anti-inflammatory agents.
  • Such compositions may be prepared by conventional methods of formulation.
  • compositions will contain 50-1000 mgs of a compound of this invention and may be taken 1-6 times daily so that the daily dose is from 200 mg to 2000 mg.
  • the compounds of this invention are substantially non-toxic as is shown by their LD 50 values in mice which are greater than lg/kg/orally.
  • the compounds of this invention show activity on standard anti-inflammatory tests such as the Cotton Pellet Granuloma Test and Carageenin Induced Oedema Test at doses in the order of 50-200 mg/kg/orally.
  • the present invention also provides a process for the preparation of the compounds of this invention which process comprises the acetalation, enol acylation or enol etherification of the compound of the formula (I): ##STR4##
  • Such reactions may be brought about under conventional reaction conditions such as reaction with an alcohol under slow dehydrating conditions, reaction with an orthoester such as an orthoformate, reaction with an isopropenyl ester and the like.
  • Such reactions will normally take place in an inert solvent such as benzene or toluene at an elevated temperature, for example at the reflux point of the mixture.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pain & Pain Management (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Rheumatology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Compounds That Contain Two Or More Ring Oxygen Atoms (AREA)

Abstract

Acetals, enol acylates and enol ethers of the compound of the compound of the formula (I): ##STR1## notionally derivable from a C1-8 alcohol or C1-8 acid are useful anti-inflammatory agents.

Description

The present invention relates to naphthalene derivatives, to pharmaceutical compositions containing them and to the process for their preparation.
The present invention provides anti-inflammatory acetals, enol acylates and enol ethers of the compound of the formula (I): ##STR2##
The compound of the formula (I) is described in Belgian Pat. No. 819794.
Suitably the aforementioned derivatives of the compounds of formula (I) are those notionally derivable from C1-8 alcohols or C1-8 acids.
Most suitably the aforementioned derivatives of the compounds of the formula (I) are those notionally derivable from C2-4 alcohols or C2-4 acids.
Particularly suitable compounds of this invention include those of the formulae (II)-(IV): ##STR3## wherein R1 is an ethyl, propyl, acetyl or propionyl group; R2 is an ethyl or propyl group and R3 is an ethyl or propyl group or is joined to R2 so that R2 together with R3 is a CH2 CH2 or CH2 CH2 CH2 group.
The present invention also provides pharmaceutical compositions adapted for oral administration which comprise an anti-inflammatory compound of the invention together with a pharmaceutically acceptable carrier.
The compositions of this invention may be in the form of tablets, capsules, solutions, suspensions, granules or the like or any other dosage form conventionally used for the oral administration of anti-inflammatory agents. Such compositions may be prepared by conventional methods of formulation.
Generally such compositions will contain 50-1000 mgs of a compound of this invention and may be taken 1-6 times daily so that the daily dose is from 200 mg to 2000 mg.
The compounds of this invention are substantially non-toxic as is shown by their LD50 values in mice which are greater than lg/kg/orally. The compounds of this invention show activity on standard anti-inflammatory tests such as the Cotton Pellet Granuloma Test and Carageenin Induced Oedema Test at doses in the order of 50-200 mg/kg/orally.
The present invention also provides a process for the preparation of the compounds of this invention which process comprises the acetalation, enol acylation or enol etherification of the compound of the formula (I): ##STR4##
Such reactions may be brought about under conventional reaction conditions such as reaction with an alcohol under slow dehydrating conditions, reaction with an orthoester such as an orthoformate, reaction with an isopropenyl ester and the like.
Such reactions will normally take place in an inert solvent such as benzene or toluene at an elevated temperature, for example at the reflux point of the mixture.
It is frequently beneficial to include a dehydration catalyst such as p-toluenesulphonic acid in the mixture.
The following Examples illustrate the invention:
EXAMPLE 1 4-(6'-Methoxy-2'-naphthyl)-2-ethylenedioxybutane
A solution of 4-(6'-methoxy-2'-naphthyl)butan-2-one (5 g), ethylene glycol (30 ml) and p-toluenesulphonic acid (0.2 g) in benzene (250 ml) was refluxed for 20 hours with constant separation of water (Dean-Stark trap). The mixture was cooled to room temperature, basified with dilute sodium bicarbonate solution (60 ml) and extracted with ether (3×100 ml). The combined organic fraction was washed with water (2×50 ml), dried and concentrated. Recrystallization of the crude solid from 40°-60° petrol gave pure 4-(6'-methoxy-2'-naphthyl)-2-ethylenedioxybutane (4.5 g) as colourless needles, m.p. 61°-9° C.
Calculated for C17 H20 O3 : C, 74.97; H, 7.40%. Found: C, 74.84 and 75.23; H, 7.55 and 7.45%.
EXAMPLE 2 4-(6'-Methoxy-2'-naphthyl)-2-ethoxybut-1-ene and 4-(6'-methoxy-2'-naphthyl)-2-ethoxybut-2-ene
A solution of 4-(6'-methoxy-2'-naphthyl)butan-2-one (5 g), ethyl orthoformate (10 g) and ethanol (10 ml) was treated with dry, saturated ethereal hydrogen chloride (5 ml) and then left at room temperature overnight. Removal of the solvents and distillation of the product at 150°-60°/0.01 mm Hg gave a colourless oil, which was chromatographed on an alumina column using 10% ethereal petrol to afford a mixture of 4-(6'-methoxy-2'-naphthyl)-2-ethoxybut-1-ene and 4-(6'-methoxy-2'-naphthyl)-2-ethoxybut-2-ene.
EXAMPLE 3 4-(6'-Methoxy-2'-naphthyl)-2-acetoxybut-1-ene and 4-(6'-methoxy-2'-naphthyl)-2-acetoxybut-2-ene
A mixture of 4-(6'-methoxy-2'-naphthyl)butan-2-one (5 g), isopropenyl acetate (250 g) and p-toluenesulphonic acid (0.5 g) was refluxed for 24 hours. The cooled solution was washed with water, dried and concentrated. The crude product was chromatographed on a silica gel column using 10ethereal petrol to give a mixture of 4-(6'-methoxy-2'-naphthyl)-2-acetoxybut-1-ene and 4-(6'-methoxy-2'-naphthyl)-2-acetoxybut-2-ene (3.5 g).

Claims (17)

What is claimed is:
1. An enol acylate of the formula ##STR5## in which R1 is alkanoyl of 2-4 carbon atoms.
2. A compound according to claim 1 of the formula (II): ##STR6## wherein R1 is acetyl or propionyl.
3. A compound according to claim 1 of the formula (III): ##STR7## wherein R1 is acetyl or propionyl.
4. The compound according to claim 1 which is 4-(6'-methoxy-2'-naphthyl)-2-acetoxybut-1-ene.
5. The compound according to claim 1 which is 4-(6'-methoxy-2'-naphthyl)-2-acetoxybut-2-ene.
6. A pharmaceutical composition for oral administration for treating inflammation in humans and animals which comprises an anti-inflammatory amount of an enol acylate of the formula ##STR8## in which R1 is alkanoyl of 2-4 carbon atoms in combination with a pharmaceutically acceptable carrier.
7. The composition according to claim 6 in unit dosage form, each dosage unit of which contains 50 to 1000 mgs of the anol acylate.
8. A composition according to claim 6 wherein the enol acylate is of the formula (II): ##STR9## wherein R1 is acetyl or propionyl.
9. A composition according to claim 6 wherein the enol acylate is of the formula (III): ##STR10## wherein R1 is acetyl or propionyl.
10. A composition according to claim 6 wherein the enol acylate is 4-(6'-methoxy-2'-naphthyl)-2-acetoxybut-1-ene.
11. A composition according to claim 6 wherein the enol acylate is 4-(6'-methoxy-2'-naphthyl)-2-acetoxybut-2-ene.
12. A method of treating inflammation in humans and animals which comprises administering orally to a human or animal in need thereof an anti-inflammatory amount of an enol acylate. ##STR11## in which R1 is alkanoyl of 2-4 carbon atoms.
13. A method according to claim 12 wherein the enol acylate is of the formula (II): ##STR12## wherein R1 is acetyl or propionyl.
14. A method according to claim 12 wherein the enol acylate is of the formula (III): ##STR13## wherein R1 is acetyl or propionyl.
15. A method according to claim 12 wherein the enol acylate is 4-(6'-methoxy-2'-naphthyl)-2-acetoxybut-1-ene.
16. A method according to claim 12 wherein the enol acylate is 4-(6'-methoxy-2'-naphthyl)-2-acetoxybut-2-ene.
17. A method according to claim 12 wherein from 200 mg to 2000 mg is administered per day.
US05/735,738 1975-10-29 1976-10-26 Pharmacologically active enol esters Expired - Lifetime US4180585A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AR26971777A AR215654A1 (en) 1976-10-26 1977-10-25 AN IMPROVED DRIVE FOR A MOBILE HARVESTER

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB44530/75A GB1497109A (en) 1975-10-29 1975-10-29 Naphthalene derivatives
GB44530/75 1975-10-29

Publications (1)

Publication Number Publication Date
US4180585A true US4180585A (en) 1979-12-25

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Country Status (5)

Country Link
US (1) US4180585A (en)
JP (3) JPS6045167B2 (en)
DE (1) DE2647966C2 (en)
FR (1) FR2329263A1 (en)
GB (1) GB1497109A (en)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4560777A (en) * 1980-02-26 1985-12-24 Blaschim S.P.A. Preparation of esters of 2-(6'-methoxy-2'-naphthyl)-propionic acid via rearrangement of ketals of 2-halo-1-(6'-methoxy-2'-naphthyl)-propan-1-one
USRE32122E (en) * 1980-06-07 1986-04-22 Bayer Aktiengesellschaft 4-substituted 3,3-dimethyl-butan-2-ones, processes for their preparation and their use as intermediate products
WO1989006226A1 (en) * 1987-12-31 1989-07-13 Quest Systems, Inc. Synthesis of 1,2-dioxetanes and intermediates therefor
US5777170A (en) * 1996-07-29 1998-07-07 Archimica Spa Process for the preparation of a naphthylbutanone
CN114072374A (en) * 2019-09-04 2022-02-18 伊士曼化工公司 Aromatic enol ethers
CN114072373A (en) * 2019-09-04 2022-02-18 伊士曼化工公司 Method for preparing aromatic enol ether and olefin isomer of aromatic enol ether

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE2963747D1 (en) * 1978-11-23 1982-11-04 Beecham Group Plc Naphthalene derivatives, a process for their preparation and their use in anti-inflammatory pharmaceutical compositions

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3923900A (en) * 1972-05-03 1975-12-02 Riker Laboratories Inc 1-(6-Methoxy-2-naphthyl)ethyl hydroxymethylketone
US3943257A (en) * 1973-08-20 1976-03-09 Sandoz, Inc. 4-Alkyl-4-naphthyl butenes

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3923900A (en) * 1972-05-03 1975-12-02 Riker Laboratories Inc 1-(6-Methoxy-2-naphthyl)ethyl hydroxymethylketone
US3943257A (en) * 1973-08-20 1976-03-09 Sandoz, Inc. 4-Alkyl-4-naphthyl butenes

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chem. Abstracts, 65:18552a. *
Chem. Abstracts, 80:36809m. *

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4560777A (en) * 1980-02-26 1985-12-24 Blaschim S.P.A. Preparation of esters of 2-(6'-methoxy-2'-naphthyl)-propionic acid via rearrangement of ketals of 2-halo-1-(6'-methoxy-2'-naphthyl)-propan-1-one
USRE32122E (en) * 1980-06-07 1986-04-22 Bayer Aktiengesellschaft 4-substituted 3,3-dimethyl-butan-2-ones, processes for their preparation and their use as intermediate products
WO1989006226A1 (en) * 1987-12-31 1989-07-13 Quest Systems, Inc. Synthesis of 1,2-dioxetanes and intermediates therefor
GR1000118B (en) * 1987-12-31 1991-06-28 Quest Systems Inc Composition 1,2-dioetans and intermediate substances for it
US5777170A (en) * 1996-07-29 1998-07-07 Archimica Spa Process for the preparation of a naphthylbutanone
CN114072374A (en) * 2019-09-04 2022-02-18 伊士曼化工公司 Aromatic enol ethers
CN114072373A (en) * 2019-09-04 2022-02-18 伊士曼化工公司 Method for preparing aromatic enol ether and olefin isomer of aromatic enol ether
CN114072374B (en) * 2019-09-04 2024-03-08 伊士曼化工公司 Aromatic enol ethers

Also Published As

Publication number Publication date
JPS628420B2 (en) 1987-02-23
GB1497109A (en) 1978-01-05
JPS6045167B2 (en) 1985-10-08
FR2329263B1 (en) 1978-12-15
JPS60214754A (en) 1985-10-28
FR2329263A1 (en) 1977-05-27
JPS60214752A (en) 1985-10-28
JPS5257154A (en) 1977-05-11
DE2647966C2 (en) 1984-12-13
JPS628421B2 (en) 1987-02-23
DE2647966A1 (en) 1977-05-12

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